A new study has identified a molecular guardian that keeps skin cells from "forgetting" what they are and transforming into aggressive, migratory killers. By stabilizing a master genetic switch, this protein shield prevents common skin tumors from undergoing a dangerous metamorphosis and spreading to the lungs.

]– Researchers at the Hebrew University of Jerusalem, led PhD student Tirza Bidany-Mizrahi under the guidance of Prof. Rami I. Aqeilan, in collaboration with Mara Mancini, Prof. Gerry Melino, Prof. Eleonora Candi from the University of Rome, have identified a biological mechanism that acts as a primary defense against the progression of aggressive skin cancer. The study, published in PNAS, explains how the loss of a specific protein called WWOX allows common skin cancer cells to transform into a more lethal, invasive form.

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer worldwide. While many cases are treatable, some tumors become highly aggressive, spreading to other parts of the body and becoming resistant to standard therapies. The findings, published in a recent manuscript, provide a new roadmap for identifying which patients are at the highest risk.

The Shield of "Epidermal Identity"
The research team found that WWOX serves as a "guardian" of what scientists call epithelial identity. In healthy skin, this protein ensures that skin cells remain stable and perform their intended functions. When WWOX is present, it stabilizes another essential protein known as p63, which acts like a master switch to keep skin cells from losing their shape and structure.

Using advanced genetic models and human tissue samples, Prof. Aqeilan’s team demonstrated that when WWOX is lost, the p63 protein levels drop significantly. This creates a "perfect storm" for cancer progression. Without these two protectors, skin cells undergo a process called epithelial-to-mesenchymal transition (EMT). Essentially, the cancer cells lose their "skin cell" identity and take on the characteristics of migratory cells, allowing them to invade deeper tissues and move through the bloodstream to the lungs and other organs.

Faster Progression and Higher Risk
The study highlights that the loss of WWOX does not just make the cancer possible; it dramatically accelerates it. In laboratory models where both WWOX and the well-known tumor suppressor p53 were missing, tumors appeared much earlier and were far more aggressive and poorly differentiated than those where WWOX was still functioning.

"WWOX deficiency significantly accelerates tumor onset and progression," Prof. Aqeilan noted, adding that 100% of the subjects in the double-deficiency group developed tumors compared to a much lower percentage in the control groups.

By examining human tissue microarrays, the team confirmed that this isn't just a laboratory phenomenon. They found a consistent pattern in human patients: as skin cancer progressed to more advanced stages, the levels of both WWOX and p63 declined in tandem. This correlation suggests that these proteins could be used as clinical biomarkers to help doctors predict which skin cancers are likely to become dangerous. Furthermore, the results suggest that targeting the WWOX–p63 axis could be a potential therapeutic approach. Interventions that focus on restoring WWOX levels, stabilizing p63, or encouraging epithelial differentiation might inhibit EMT and slow down tumor growth.